PROJECT SUMMARY/ABSTRACT: Background: Irritability is: the most common reason children and adolescents are brought for psychiatric care, associated with significant impairment in childhood and subsequently in adulthood, a symptom found in many DSM-categorical disorders?yet we have no clinically useful, validated bio-behavioral marker or measure to guide clinician's diagnosis or treatment of children presenting with irritability. To address this problem, the 2014 NIMH Pediatric Irritability Workshop and the 2015 1st Congress on Pediatric Irritability heralded the need for greater research on brain/behavior mechanisms of pediatric irritability, including studies in trans-diagnostic samples drawn across the range of impairment, rather than a single DSM disorder and testing multiple dimensional irritability assessments. Previously, we have investigated the brain/behavior alterations underlying cognitive flexibility?defined as behavioral adaptation in response to changing rewards and punishments?as one potential mechanism underlying irritability in children meeting categorical definitions of bipolar disorder (episodes of euphoria and irritability) or severe mood dysregulation (chronic irritability) vs. controls. Now, we seek to take the next step in this line of research. The objective of this application is to define the brain/behavior mechanism-based sub-types of irritability and cognitive flexibility in a trans-diagnostic sample of children ages 8-12 drawn across the range of impairment. Our central methodology is to test how circuit and behavior alterations in cognitive flexibility identify different sub-types of irritability, using single time point irritability questionnaires/interviews and a novel multi-time point irritability ecological momentary assessment (EMA) Android app, and harnessing novel computational psychiatry analytic techniques to determine which model best explains brain/behavior-based clusters of irritability. Our central hypothesis is that all irritability does not result from a single mechanism; rather unique symptom clusters of irritability result from specific PFC- temporo-striatal circuit alterations mediating cognitive flexibility. The rationale for this proposal is that greater understanding of the biological mechanisms underlying cognitive flexibility and irritability symptoms will lead to novel brain-based classification and treatments for children suffering from irritability. Our study is innovative because we will be the first to identify the brain/behavior mechanisms underlying irritability and cognitive flexibility using (1) a trans-diagnostic sample of children drawn across levels of care and impairment, rather than DSM categorical disorder(s), (2) novel EMA-irritability app, (3) computational psychiatry analytic techniques, and (4) fMRI/behavioral tasks drawn from BD/SMD research plus the RDoC matrix. Our study is both significant and clinically meaningful because greater understanding of the brain/behavior mechanisms of irritability and cognitive flexibility is critical to achieving the ultimate goal of a precision medicine approach for irritability?whereby bio-behavioral markers (scans and tests) are used for more specific/earlier classification and diagnosis plus biologically-guided treatment (e.g., medications, cognitive remediation, and TMS/TDCS).